PROJECT SUMMARY: Earlier versions of this R01 grant focused on the role of transcription factors inmediating depression-related behavioral abnormalities in animal models. We werethe first to implicate CREB in stress models and antidepressant responses. Morerecently, over the past 10 years, we have similarly defined the actions of FosB indetermining an animal's susceptibility vs. resilience to chronic stress. We have alsoused a range of genome-wide assays to define the target genes of these transcriptionfactors. These evolving datasets suggest the central involvement of glutamatergicneurotransmission within the nucleus accumbens (NAc), a key brain reward region,in governing these distinct responses to stress. Thus, for this competitive renewalapplication, we propose to utilize this novel insight to define how alteredglutamatergic signaling in NAc controls stress susceptibility vs. resilience. We usestate-of-the-art optogenetic tools to activate or suppress specific glutamatergicinputs to NAc and investigate the effect of these manipulations on both thedevelopment of stress-related behavioral abnormalities as well as their expression.We present robust preliminary evidence that different glutamatergic inputs alterstress vulnerability in very different ways. For example, acute optogeneticactivationof the prelimbic prefrontal cortex (PFC) promotes resilience, while acute activationof the ventral subiculum (vSUB) or medial thalamus promotes susceptibility. Asanother example, induction of long-term depression (LTD) specifically at vSUBsynapses dramatically enhances resilience, while LTD at infralimbic PFC synapsesmay enhance susceptibility. These data set the stage for a uniquely comprehensiveanalysis of how different glutamatergic inputs to NAc differentially control stressresponses. The second part of this R01 investigates the role of several prominenttarget genes, arising from our genome-wide assays and not previously implicated instress responses, in mediating post- and presynaptic forms of glutamatergicplasticity in NAc. Together, the proposed studies will shed fundamental light oncircuit-level mechanisms in stress susceptibility and resilience, and validate a seriesof new targets for the development of better treatments for depression and otherstress-related disorders.